Extracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness.

Abstract

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.

• Authors: Huijing Yin, Jingshu Wang, Hui Li, Yinjue Yu, Xiaoling Wang, Lili Lu, Cuiting Lv, Bin Chang, Wei Jin, Wenwen Guo, Chunxia Ren, Gong Yang
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 4230 (07 09 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34244494 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• ABCG1 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ECM1 protein, human
• Extracellular Matrix Proteins
• HNRNPLL protein, human
• Heterogeneous-Nuclear Ribonucleoproteins
• Integrin alphaXbeta2
• Protein Isoforms
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 1 (genetics)
• Alternative Splicing
• Animals
• Carcinoma, Ovarian Epithelial (genetics, mortality, pathology, therapy)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• Cisplatin (pharmacology, therapeutic use)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• Extracellular Matrix Proteins (genetics, metabolism)
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Heterogeneous-Nuclear Ribonucleoproteins (genetics)
• Humans
• Integrin alphaXbeta2 (genetics, metabolism)
• Kaplan-Meier Estimate
• Mice
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local (epidemiology, genetics, pathology)
• Neoplastic Stem Cells (pathology)
• Ovarian Neoplasms (genetics, mortality, pathology, therapy)
• Ovary (pathology, surgery)
• Phosphorylation (genetics)
• Prognosis
• Protein Isoforms (genetics, metabolism)
• RNA-Seq
• Signal Transduction (genetics)
• Xenograft Model Antitumor Assays